1. Field of the Invention
The invention relates to homogeneous preformulations containing high concentration of steroids, for producing low-dose solid and semi-solid pharmaceutical preparations having a concentration content of 0.001 to 1 weight percent of steroid.
2. Prior Art
The invention also relates to a method for producing the homogeneous preformulations, containing steroids in high concentration, for the claimed low-dose solid and semi-solid pharmaceutical preparation.
It is known that the homogeneous distribution of active ingredients is an essential prerequisite for the reliable effect of a medication.
The problem of homogeneous active ingredient distribution arises especially in single-dose solid and semi-solid forms of preparation in which the active ingredient is not in dissolved form, such as in tablets, lozenges, capsules and suppositories.
The prerequisite for the homogeneous distribution of active ingredients in the single-dose forms of medication is on the one hand a uniform distribution of the active ingredient in the basic mixture or preformulation and on the other the preservation of this distribution during further processing. Nonhomogeneities in the mixture of active ingredients and adjuvants and inaccuracies in further processing are added together and lead to fluctuations in dosage in solid and semi-solid single dose forms of medication.
In high-dose preparations, as a rule no serious mixing nonhomogeneities occur.
In low-dose forms of medication, the primary problem is to furnish a sufficiently homogeneous distribution, which is stable against demixing, of the very low mass of active ingredient in proportion to the mass of the pharmaceutical adjuvants.
From the professional and patent literature, low-dose solid and semi-solid preparations containing steroids are known; the preformulations are produced by means of dry and moist granulation technologies or dry mixing processes.
M. Dittgen, H. Kala et. al., for instance, in "Zur pharmazeutischen Technologie der Granulierung" [On the pharmaceutical technology of granulation], Pharmazie 35, 4, pages 237 to 249, 1980, describe such granulation technologies.
It is problematic by means of the mixing process to achieve good content uniformity while avoiding demixing and sizing effects, for instance from defluidizing and outgassing of fine active ingredient particles from the fluidized bed.
Formulations produced by these technologies have the disadvantages of
the use of micronized active ingredients and the attendant necessity of one additional process step; PA1 derived from this the possibility of recrystallization and clumping by way of the active surfaces of the active ingredient particles and the attendant negative effects on homogeneity and release properties. PA1 the occurrence of deviations from the desired steroid content by outgassing of fine steroidal abrasion from the fluidized bed; PA1 the fact that because of the long dwell times in the production process, undesired decomposition processes can occur in thermally unstable active ingredients. PA1 Only selected excipients have the requisite adsorptive properties; PA1 The loading capacity of the surfaces is only very limited; PA1 for coating medication particles with protective casings and for modifying the physical properties of the active ingredients and adjuvants, with the goal of making their further processing (such as tablets) easier. PA1 because of the large particle size of these granulates, the requisite content uniformity does not always exist through subsequent mixing; PA1 the spray granulation of the necessarily highly dilute steroid solutions or suspensions is very complicated and expensive, because of the large volumes involved. PA1 a) dissolving steroid or steroid ingredients in a solvent to form a dispersant; PA1 b) dispersing an adjuvant consisting of adjuvant particles in the dispersant in a mass ratio of adjuvant to the steroid or steroid ingredients of 1:1 to 1000:1 to form a suspension; and PA1 c) creating a spray-mist of the suspension so as to evaporate and remove the solvent from the suspension and thus to form a dried particulate comprising a plurality of steroid-containing particles, the spray mist comprising a plurality of droplets having a droplet diameter greater than a mean diameter of the adjuvant particles; PA1 Very good, stable active ingredient homogeneity in the pharmaceutical preparation for tableting. PA1 The limit particle size of the preformulation, which is important for subsequent mixing processes, is defined by the choice of the adjuvant particle size, since this particle size is increased only insignificantly (see Examples 1-3 and Tables 3-5) by the spraying on of the active ingredient. PA1 Nonhomogeneities and demixing or sizing effects during the subsequent mixing process are thus avoided. PA1 The advantageous galenic properties of the adjuvant are transferred to the preformulation, and the solid properties of the active ingredient are stabilized. PA1 Clumping and attendant changes in activity, as are often observed in micronized steroids, did not occur. PA1 The use of micronized steroids can be dispensed with. This means that one complicated process step can be eliminated. Micronized steroid active ingredients, such as desogestrel, often have a tendency to later recrystallization and clumping effects, which are deleterious to the active ingredient homogeneity and release. PA1 At the same time, the influence of crystallization in producing the active ingredient, or in other words the often complicated definition and validation of the crystal structure and crystallinity, is averaged out. PA1 The preformulations are stable to demixing and can be stored. PA1 By the spray drying of the suspension droplets (adjuvant particles sheathed with active ingredient solution), which are finely distributed in a drying gas, via a nozzle or atomizer disk, a material and finely dispersed bonding of the active ingredient with the adjuvant surface is attained by a rapid evaporation of the solvent. As a result the adsorptive properties of the adjuvant, which in the prior art are decisive for dry mixing with micronized steroids and which substantially restrict the selection of adjuvants, are of only secondary importance. PA1 The loading of the adjuvant with active ingredients can be substantially greater than in mechanical mixing of the adjuvant with micronized steroids. PA1 In common with the dissolved steroid and suspended adjuvant, other adjuvants that improve stability, speed up resorption or modify the release kinetics and that can be present in dissolved or suspended form can be spray dried. PA1 Incorporating these adjuvants already in the preformulation stage makes the mixing stage of the pharmaceutical final formulation easier extends the above-discussed advantages of spray drying with regard to the steroid distribution on the adjuvant to these adjuvants as well. PA1 It is also possible, for instance by using suitable soluble adjuvants, to embed the active ingredient in molecularly dispersed form in the adjuvant sheath and thus to speed up or slow down the release or to protect the active ingredient against the environment. PA1 By way of the spray process, more galenic possibilities are thus opened up than by way of dry mixing of micronized steroids and adjuvants. PA1 The spray drying process, since the evaporation of the solvent takes place within fractions of a second, is an extremely gentle process precisely for thermally vulnerable steroids (such as sulfamate steroids). PA1 The above-discussed advantages allow the flexible production of steroidal preformulations with specific galenic properties as for the pharmaceutical final formulation of the tablet composition. PA1 The galenic complication and the pharmaceutical technology for the final formulation are drastically reduced and simplified. PA1 The preformulations produced in a preliminary step, heavily loaded with steroid and thus low in quantity, can be processed without problems by the dry mixing process to produce very homogeneous tablets with the usual tableting adjuvants.
In a special form of the fluidized bed-spray granulation process, the use of micronized active ingredients is circumvented by dissolving the active ingredient in an organic solvent at high dilution and spraying it onto a large-particle adjuvant moving in a fluidized bed and granulating it by building on that structure.
The disadvantages of the formulations produced by this method are:
One disadvantage of the method that should not be underestimated is that large quantities of solvent are in the final steps of the galenic preparation, which requires major effort and expense for equipment and safety technology (explosion proofing together with rendering nitrogen inert).
In European patent disclosure EP 0 503 521, it is described that a direct-tabletable pharmaceutical preparation is attained by dry mixing of micronized steroids with certain excipients (spray-dried lactose).
This proves to have the following disadvantages:
once again, micronized active ingredients are used, which have the disadvantage of recrystallization and clumping along the active surfaces of the active ingredient particles and the attendant negative effects on homogeneity and release properties.
M. Dekker, in "The spray drying of pharmaceuticals", Drug Development and Industrial Pharmacy", 18 (11 & 12) pages 1169 through 1206, 1992, and
E. Nurnberg, in "Darstellung und Eigenschaften pharmazeutisch relevanter Spruhtrocknungsprodukte" [Characterization and properties of pharmaceutically relevant spray drying products], Acta Pharmazeutica Technologica, 26(1), pages 40 to 67, 1980 describe the use of spray drying technology for the galenic formulation of pharmaceutical active ingredients, including steroids.
With the spray drying, primarily retardant effects or effects that improve solubility and stability are attained by way of active ingredient imbedding or microencapsulations (for instance in polymeric adjuvants) or inclusion complexes (in cyclodextrins).
According to J. Cooper and J. E. Rees, "Tableting research and technology" J. Pharm. Sci. 61 (1972) pages 1551 to 1555, the spray drying can be used
According to H. Kala et.al., "The use of spray drying in pharmacy", Pharmazie, 34, No. 12 (1979) pages 779 to 784, the use of spray drying for attaining certain properties in active ingredients and adjuvants that go beyond simple drying and simultaneous micronization is fundamentally known.
For example, metastable medication modifications or amorphous active ingredients can be produced in standardized fashion, in order to improve the speed of dissolution or to preclude uncertainty factors dictated by the existence of various crystal modifications.
In this connection, spray imbedding in various adjuvants and spray drying of suspensions of a solution of medication and insoluble adjuvant (celluloses) are mentioned in particular.
H. Kala et.al. also mention that spray products (adjuvants as dry binders, active ingredients, and combinations) in the form of spherical, free-flowing particles have already been used for direct tableting.
M. Dekker, in "The spray drying of pharmaceuticals", Drug Development and Industrial Pharmacy, 18 (11 & 12) pages 1169 through 1206, 1992, mentions that fine, free-flowing adjuvant granulates (fillers, binders, explosives, pigments) for direct tableting can be produced by spray drying.
The goal of this spray granulation process is to attain more favorable processing properties, which however as a rule are associated with an increased particle size, for direct tableting.
The disadvantage of these technologies with a view to direct production of low-dose pharmaceutical preparations is as follows: